Radiotherapy (RT) can trigger immunogenic cell death (ICD) in tumor cells and release adenosine triphosphate (ATP) to activate antitumor immunity. However, the formation of immunosuppressive adenosine (ADO) mediated by ectonucleotidases including CD39 and CD73, can exacerbate the immunosuppressive effects. Herein, a radiosensitizer-based metal-organic framework (MOF) composed of bismuth (Bi) and ellagic acid (EA) was synthesized in situ on the surface of Escherichia coli Nissle 1917 (EcN) to serve as a carrier for the CD39 inhibitor sodium polyoxotungstate (POM-1). This therapeutic platform, acting as a radiosensitizer, significantly enhances cytotoxicity against tumor cells while effectively inducing ICD and releasing high concentrations of ATP. Subsequently, the released POM-1 increases the levels of pro-inflammatory extracellular ATP while preventing tumor immunosuppression caused by the accumulation of ADO. Additionally, as a natural immune adjuvant, EcN further promotes the maturation of dendritic cells (DCs) and the infiltration of cytotoxic T lymphocytes (CTLs). As a result, such treatment initiates the destruction of established tumor growth and induces strong abscopal effects, leading to a significant inhibition of tumor metastases. This strategy presents a bacterial-based biohybrid system that facilitates RT-induced ICD while simultaneously limiting the degradation of ATP into ADO, thereby achieving sustained anti-tumor immunity.

Cuproptosis, a copper-dependent form of regulated cell death, has been implicated in the progression and treatment of various tumors. The copper ionophores, such as Disulfiram (DSF), an FDA-approved drug previously used to treat alcohol dependence, have been found to induce cuproptosis. However, the limited solubility and effectiveness of the combination of DSF and copper ion restrict its widespread application. In this study, through a random screening of our in-house compound library, we identified a novel cuproptosis inducer, YL21, comprising a naphthoquinone core substituted by two dithiocarbamate groups. The combination of YL21 with copper ion induces cuproptosis by disrupting mitochondrial function and promoting the oligomerization of lipoylated protein DLAT. Further, this combination induces endoplasmic reticulum (ER) stress and oxidative stress, triggering immunogenic cell death (ICD) and subsequently promoting the activation of antitumor immune responses to suppress tumor growth in the mice breast cancer model. Notably, the combination of YL21 and copper ion demonstrated improved solubility and increased antitumor activity compared to the combination of DSF and copper ion. Thus, YL21 functions as a novel cuproptosis inducer and may serve as a promising candidate for antitumor immunotherapy.

The induction of apoptosis in tumor cells is a common target for the development of anti-tumor therapies; however, these therapies still leave patients at increased risk of disease recurrence. For example, apoptotic tumor cells can promote tumor growth and immune evasion via the secretion of metabolites, apoptotic extracellular vesicles, and induction of pro-tumorigenic macrophages. This paradox of apoptosis induction and the pro-tumorigenic effects of tumor cell apoptosis has begged the question of whether apoptosis is a suitable cancer therapy, and led to further explorations into other immunogenic cell death-based approaches. However, these strategies still face multiple challenges, the most critical of which is the tumor microenvironment. Contrary to the promotion of immune tolerance mediated by apoptotic tumor cells, apoptotic bodies with enriched tumor-related antigens have demonstrated great immunogenic potential, as evidenced by their ability to initiate systemic T-cell immune responses. These characteristics indicate that apoptotic body-based therapies could be ideal "in situ" extra-tumoral tumor vaccine candidates for the treatment of cancers, and further address the current issues with apoptosis-based or immunotherapy treatments. Although not yet tested clinically, apoptotic body-based vaccines have the potential to better treatment strategies and patient outcomes in the future.

The purinergic P2Y receptors comprise eight G-coupled receptor (GPCR) subtypes already identified (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12-14). P2Y receptor physiological agonists are extracellular purine and pyrimidine nucleotides such as ATP (Adenosine triphosphate), ADP (Adenosine diphosphate), UTP (Uridine triphosphate), UDP (Uridine diphosphate), and UDP-glucose. These receptors are expressed in almost all cells. P2Y receptors are found in immune cells, such as macrophages, neutrophils, mast cells, dendritic cells, and lymphocytes. P2Y receptors play essential roles in inflammation and are involved in several cell processes, including efferocytosis, phagocytosis, chemotaxis, degranulation, killing pathogens, cytokine production, and platelet aggregation. These processes underpin immune responses against pathogens. Therefore, here we discuss P2Y receptor pharmacology and mechanisms triggered by the activation of these receptors in virus, bacteria, and parasite infections. In addition, we highlight the therapeutical potential of P2Y receptors for developing new pharmacological strategies to modulate inflammation and disease outcomes in pathogen infections.

A significant challenge in the treatment of melanoma with immune checkpoint blockades (ICBs) is the limited T cells response often observed in immunologically "cold" tumors. By leveraging the immunogenicity of immunogenic cell death (ICD), which increases the susceptibility of tumor cells to ICBs, this study investigated the potential of a nucleus-targeted ruthenium(II) complex (Ru1) as an inducer of ICD. Treatment with Ru1 induced DNA damage in melanoma cells, activating the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway. This triggered endoplasmic reticulum (ER) stress, leading to ICD. Ru1-treated dying melanoma cells exhibited characteristics such as cell exposure of calreticulin (CRT) on the cell surface, release of adenosine triphosphate (ATP), and secretion of high-mobility group box 1 (HMGB1). Vaccination with Ru1-treated, dying melanoma cells elicited robust antitumor immune responses, as evidenced by CD8+ T cells activation, reduced Foxp3+ T cells count, and the development of a memory immune response that protected mice from subsequent melanoma challenges. Combining Ru1 with anti-PD-1 therapy significantly promoted T cells infiltration, enhanced dendritic cell activation, and reduced tumor-associated immunosuppressive factors, indicating a reprogramming of the tumor microenvironment. These findings suggest that Ru1 is a promising therapeutic agent for treating "cold" tumors in cancer chemoimmunotherapy.

The complex nature of pain pathophysiology complicates the establishment of objective diagnostic criteria and targeted treatments. The heterogeneous manifestations of pain stemming from various primary diseases contribute to the complexity and diversity of underlying mechanisms, leading to challenges in treatment efficacy and undesirable side effects. Recent evidence suggests the presence of apoptotic cells at injury sites, the distal dorsal root ganglia (DRG), spinal cord, and certain brain regions, indicating a potential link between the ineffective clearance of dead cells and debris and pain persistence. This review highlights recent research findings indicating that efferocytosis plays a significant yet often overlooked role in lesion expansion while also representing a potentially reversible impairment that could be targeted therapeutically to mitigate chronic pain progression. We examine recent advances into how efferocytosis, a process by which phagocytes clear apoptotic cells without triggering inflammation, influences pain initiation and intensity in both human diseases and animal models. This review summarizes that efferocytosis contributes to pain progression from the perspective of defective and inefficient efferocytosis and its subsequent secondary necrocytosis, cascade inflammatory response, and the shift of phenotypic plasticity and metabolism. Additionally, we investigate the roles of newly discovered genetic alterations or modifications in biological signaling pathways in pain development and chronicity, providing insights into innovative treatment strategies that modulate efferocytosis, which are promising candidates and potential avenues for further research in pain management and prevention.

Immunotherapy has transformed cancer treatment paradigms, but its effectiveness depends largely on the immunogenicity of the tumor. Unfortunately, the high resemblance of cancer to normal tissues makes most tumors immunologically 'cold', with a poor response to immunotherapy. Danger signals are critical for breaking immune tolerance and mobilizing robust, long-lasting antitumor immunity. Recent studies have identified inflammatory cell death modalities and their power in providing danger signals to trigger optimal tumor suppression. However, key mediators of inflammatory cell death are preferentially silenced during early tumor immunoediting. Strategies to rejuvenate inflammatory cell death hold great promise for broadening immunotherapy-responsive tumors. In this review, we examine how inflammatory cell death enhances tumor immunogenicity, how it is suppressed during immunoediting, and the potential of harnessing it for improved immunotherapy.

The rising aging population and changing lifestyles have led to a global increase in diabetes and its complications, making it one of the most prevalent diseases worldwide. Chronic inflammation is a key pathogenic feature of diabetes and its complications, yet the precise mechanisms remain unclear, impeding the development of targeted therapies. Recent studies have highlighted the β cell-macrophage crosstalk pathway as a crucial factor in chronic low-grade inflammation and glucose homeostasis imbalance in both type 1 and type 2 diabetes. Furthermore, impaired macrophage phagocytic functions, including pathogen phagocytosis, efferocytosis, and autophagy, play a significant role in diabetes complications. Given their high plasticity, macrophages represent a promising research target. This review summarizes recent findings on macrophage phagocytic dysfunction in diabetes and its complications, and explores emerging therapies targeting macrophage phagocytic function. We also discuss the current challenges in translating basic research to clinical practice, aiming to guide researchers in developing targeted treatments to regulate macrophage status and phagocytic function, thus preventing and treating metabolic inflammatory diseases.

Glioblastoma multiforme (GBM) is one of the most lethal malignant brain tumors in the central nervous system. Patients face many challenges after surgery, including tumor recurrence, intracranial pressure increase due to cavitation, and limitations associated with immediate postoperative oral chemotherapy. Here an injected peptide gel with in situ immunostimulatory functions is developed to coordinate the regulation of glutamine metabolism and chemodynamic therapy for overcoming these postoperative obstacles. The methodology entails crafting injectable gel scaffolds with short peptide molecules, incorporating the glutaminase inhibitor CB-839 and copper peptide self-assembled particles (Cu-His NPs) renowned for their chemodynamic therapy (CDT) efficacy. By fine-tuning glutamic acid production via metabolic pathways, this system not only heightens the therapeutic prowess of copper peptide particles in CDT but also escalates intracellular oxidative stress. This dual mechanism culminates in augmented immunogenic cell death within glioblastoma multiforme cells and improves a conducive immune microenvironment. Based on the concept of metabolic reprogramming, this treatment strategy has great potential to significantly reduce GBM tumor recurrence and prolong median survival in murine models.

This study aimed to elucidate the transcriptomic signatures and dysregulated pathways associated with the autoimmune response in Cd38-/- mice compared to wild-type (WT) mice within the bm12 chronic graft-versus-host disease (cGVHD) lupus model. We conducted bulk RNA sequencing on peritoneal exudate cells (PECs) and spleen cells (SPC) at two and four weeks following adoptive cell transfer. We also analyzed cells from healthy, untreated mice. These analyses revealed a sustained upregulation of a transcriptional profile of purinergic receptors and ectonucleotidases in cGVHD WT PECs, which displayed a coordinated expression with several type I interferon-stimulated genes (ISGs) and with key molecules involved in the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, two hallmarks in the lupus pathology. A second purinergic receptor transcriptomic profile, which included P2rx7 and P2rx4, showed a coordinated gene expression of the components of the NLRP3 inflammasome with its potential activators. These processes were transcriptionally less active in cGVHD Cd38-/- PECs than in WT PECs. We have also shown evidence of a distinct enrichment in pathways signatures that define processes such as Ca2+ ion homeostasis, cell division, phagosome, autophagy, senescence, cytokine/cytokine receptor interactions, Th17 and Th1/Th2 cell differentiation in Cd38-/- versus WT samples, which reflected the milder inflammatory and autoimmune response elicited in Cd38-/- mice relative to WT counterparts in response to the allogeneic challenge. Last, we have shown an intense metabolic reprogramming toward oxidative phosphorylation in PECs and SPC from cGVHD WT mice, which may reflect an increased cellular demand for oxygen consumption, in contrast to PECs and SPC from cGVHD Cd38-/- mice, which showed a short-lived metabolic effect at the transcriptomic level. Overall, these findings support the pro-inflammatory and immunomodulatory role of CD38 during the development of the cGVHD-lupus disease.

To visualize and analyze the trends and hotspots of efferocytosis and inflammation via bibliometric methods.

Relevant articles and reviews from 2006 to 2023 were retrieved from the Web of Science Core Collection. The data were processed with CiteSpace, and some graphs were generated with Microsoft Excel (version 2016), VOSviewer, Scimago Graphica, Bibliometrix and R Studio.

A total of 1,003 papers were included, revealing a significant upward trend in efferocytosis and inflammation research. The United States (456, 45.46%), China (164, 16.35%) and the United Kingdom (99, 9.87%) were the three countries with the highest numbers of publications. Harvard University (84, 6.74%) contributes the most out of the top 5 institutions. Among the researchers in this field, Serhan CN was the author with the highest number of articles in the field (35, 3.49%), and deCathelineau AM first named "efferocytosis" in 2003. Keyword analysis identified "activation," "tam receptors," "docosahexaenoic acid" "systemic lupus erythematosus," "myocardial infarction" and "alveolar macrophages" as core topics, indicating a concentrated trend in the mechanism of physiological state and inflammatory diseases such as autoimmune, cardiovascular, and pulmonary diseases. The latest surge words "inflammation resolution" and "cancer" in the keyword heatmap indicate future research directions.

Research on the association between efferocytosis and inflammation has been a promising field. Key areas of focus include the crucial role of efferocytosis on tissue homeostasis and the pathogenesis of nontumorous inflammatory diseases. Future research will likely continue to explore these frontiers, with an emphasis on understanding efferocytosis in the context of chronic diseases and cancer, as well as developing novel therapeutic strategies.

Dendritic cells (DCs) are specialized antigen-presenting cells that are present at low abundance in the circulation and tissues; they serve as crucial immune sentinels by continually sampling their environment, migrating to secondary lymphoid organs and shaping adaptive immune responses through antigen presentation. Owing to their ability to orchestrate tolerogenic or immunogenic responses to a specific antigen, DCs have a pivotal role in antitumour immunity and the response to immune checkpoint blockade and other immunotherapeutic approaches. The multifaceted functions of DCs are acquired through a complex, multistage process called maturation. Although the role of inflammatory triggers in driving DC maturation was established decades ago, less is known about DC maturation in non-inflammatory contexts, such as during homeostasis and in cancer. The advent of single-cell technologies has enabled an unbiased, high-dimensional characterization of various DC states, including mature DCs. This approach has clarified the molecular programmes associated with DC maturation and also revealed how cancers exploit these pathways to subvert immune surveillance. In this Review, we discuss the mechanisms by which cancer disrupts DC maturation and highlight emerging therapeutic opportunities to modulate DC states. These insights could inform the development of DC-centric immunotherapies, expanding the arsenal of strategies to enhance antitumour immunity.

Neutrophils, the most abundant circulating leukocytes, have long been recognized as key players in innate immunity and inflammation. However, recent discoveries unveil their remarkable heterogeneity and plasticity, challenging the traditional view of neutrophils as a homogeneous population with a limited functional repertoire. Advances in single-cell technologies and functional assays have revealed distinct neutrophil subsets with diverse phenotypes and functions and their ability to adapt to microenvironmental cues. This review provides a comprehensive overview of the multidimensional landscape of neutrophil heterogeneity, discussing the various axes along which diversity manifests, including maturation state, density, surface marker expression, and functional polarization. We highlight the molecular mechanisms underpinning neutrophil plasticity, focusing on the complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications that shape neutrophil responses. Furthermore, we explore the implications of neutrophil heterogeneity and plasticity in physiological processes and pathological conditions, including host defense, inflammation, tissue repair, and cancer. By integrating insights from cutting-edge research, this review aims to provide a framework for understanding the multifaceted roles of neutrophils and their potential as therapeutic targets in a wide range of diseases.

Recent research has shed light on the intricate connection between efferocytosis and infertility, revealing its dysregulation as a contributing factor in various reproductive diseases. Despite the multifaceted nature of infertility etiology, the impact of insufficient clearance of apoptotic cells on fertility has emerged as a focal point. Notably, the removal of apoptotic cells through phagocytosis in the female reproductive system has been a subject of extensive investigation in the field of infertility. Additionally, special functions performed by immune system cell types, such as macrophages and Sertoli cells, in the male reproductive system underscore their significance in spermatogenesis and the efferocytosis of apoptotic germ cells. Dysregulation of efferocytosis emerges as a critical factor contributing to reproductive challenges, such as low pregnancy rates, miscarriages, and implantation failures. Moreover, defective efferocytosis can lead to compromised implantation, recurrent miscarriages, and unsuccessful assisted reproductive procedures. This review article aims to provide a comprehensive overview of efferocytosis in the context of infertility. Molecular mechanisms underlying efferocytosis, its relevance in both female and male infertility, and its implications in various reproductive diseases are elucidated. The elucidation of the intricate relationship between efferocytosis and infertility not only facilitates diagnosis but also paves the way for targeted therapeutic interventions.

From embryogenesis to aging, billions of cells perish daily in mammals. The multistep process by which phagocytes engulf these deceased cells without eliciting an inflammatory response is called efferocytosis. Despite significant insights into the fundamental mechanisms of efferocytosis, its implications in disorders such as aging and cancer remain elusive. Upon summarizing and analyzing existing studies on efferocytosis, it becomes evident that efferocytosis is our friend in resolving inflammation, yet it transforms into our foe by facilitating tumor development and metastasis. This review illuminates recent discoveries regarding the emerging mechanisms of efferocytosis in clearing apoptotic cells, explores its connections with aging, examines its influence on tumor development and metastasis, and identifies the regulatory factors of efferocytosis within the tumor microenvironment. A comprehensive understanding of these efferocytosis facets offers insights into crucial physiological and pathophysiological processes, paving the way for innovative therapeutic approaches to combat aging and cancer.

Efferocytosis is a mechanism by which phagocytes efficiently clear apoptotic cells, averting their secondary necrosis and the subsequent release of potentially immunogenic or cytotoxic substances that can trigger strong immune and inflammatory responses. During efferocytosis, the metabolic pathways of phagocytes are transformed, which, along with the catabolism of apoptotic cargo, can affect their function and inflammatory state. Extensive apoptosis occurs during placental development, and some studies reported the immunomodulatory effects of efferocytosis at the maternal-fetal interface. The dysregulation of efferocytosis is strongly linked to pregnancy complications such as preeclampsia and recurrent spontaneous abortion. In this review, we discuss the mechanisms of efferocytosis and its relationships with metabolism and inflammation. We also highlight the roles of professional and non-professional phagocytes in efferocytosis at the maternal-fetal interface and their impact on pregnancy outcomes and explore relevant regulatory factors. These insights are expected to guide future basic research and clinical strategies for identifying efferocytosis-related molecules as potential predictors or therapeutic targets in obstetric diseases.

The parasite of the genus Leishmania is the causative agent of diseases that affect humans called leishmaniasis. These diseases affect millions of people worldwide and the currently existing drugs are either very toxic or the parasites acquire resistance. Therefore, new elimination mechanisms need to be elucidated so that new therapeutic strategies can be developed. Much has already been discussed about the role of neutrophils in Leishmania infection, and their participation is still controversial. A recent study showed that receptors present in the neutrophil membrane, the purinergic receptors, can control the infection when activated, but the triggering mechanism has not been elucidated. In this review, we will address the possible participation of purinergic receptors expressed in the neutrophil extracellular membrane that may be participating in the detection of Leishmania infection and their possible effects during parasitism.

The two main glial cell types of the central nervous system (CNS), astrocytes and microglia, are responsible for neuroimmune homeostasis. Recent evidence indicates astrocytes can participate in removal of pathological structures by becoming phagocytic under conditions of neurodegenerative disease when microglia, the professional phagocytes, are impaired. We hypothesized that adenosine triphosphate (ATP), which acts as damage-associated molecular pattern (DAMP), when released at high concentrations into extracellular space, upregulates phagocytic activity of human astrocytes. This study is the first to measure changes in phagocytic activity and mitochondrial respiration of human astrocytic cells in response to extracellular ATP. We demonstrate that ATP-induced phagocytic activity of U118 MG astrocytic cells is accompanied by upregulated mitochondrial oxidative phosphorylation, which likely supports this energy-dependent process. Application of a selective antagonist A438079 provides evidence identifying astrocytic purinergic P2X7 receptor (P2X7R) as the potential regulator of their phagocytic function. We also report a rapid ATP-induced increase in intracellular calcium ([Ca2+]i), which could serve as regulator of both the phagocytic activity and mitochondrial metabolism, but this hypothesis will need to be tested in future studies. Since ATP upregulates interleukin (IL)-8 secretion by astrocytes but has no effect on their cytotoxicity towards neuronal cells, we conclude that extracellular ATP affects only specific functions of astrocytes. The selectivity of P2X7R-dependent regulation of astrocyte functions by extracellular ATP could allow targeting this receptor-ligand interaction to upregulate their phagocytic function. This could have beneficial outcomes in neurodegenerative disorders, such as Alzheimer's disease, that are characterized by reactive astrocytes and defective phagocytic processes.

The limited replicative potential of primary hepatocytes (Hep) is a major hurdle for obtaining sufficient quantity and quality hepatocytes during cell therapy in patients with liver failure. Intrahepatic cholangiocyte organoids (ICOs) derived from intrahepatic bile ducts differentiate into both hepatocytes and cholangiocytes in vitro. Here, we studied in vivo effects of transplanting ICOs and Hep in chronic liver injury mice models. Well characterized primary mouse ICOs and Hep were mixed in decellularized liver (DCL) matrix hydrogels and injected into the subcapsular left lateral liver lobe of CCl4-induced liver injury models whereas mice given DCL alone were in the sham group. Two weeks post-transplantation, transplanted liver lobes were collected and studied by histology and RNA sequencing. Transplanted animals did not exhibit any tumors, mortality or morbidity. Mice livers transplanted with ICOs had increased cellular proliferation and vascularization as compared to Hep transplanted mice or sham. Collagen deposition in the liver was significantly reduced and serum albumin levels were significantly increased in transplanted groups compared to the sham group. Expression of genes associated with hepatocyte differentiation was highest in Hep transplanted livers among the three groups, but they were also upregulated in ICO transplanted livers compared to sham. Our study demonstrates that ICOs encapsulated in DCL hydrogels when transplanted in chronically injured mice livers engraft well and show hepatocyte differentiation and reduction of fibrosis, indicating that hydrogel transplanted cholangiocyte organoids may serve as an efficient cell source and therapy for renewal of hepatocytes, restoration of hepatocyte functions and resolution of liver injury.

Consolidation with PD-1/PD-L1-based immune checkpoint blockade after concurrent platinum-based chemo-radiotherapy has become the new standard of care for advanced stage III unresectable non-small cell lung cancer (NSCLC) patients. In order to further improve therapy outcomes, innovative combinatorial treatment strategies aim to target additional immunosuppressive barriers in the tumor microenvironment such as the CD73/adenosine pathway. CD73 and adenosine are known as crucial endogenous regulators of lung homeostasis and inflammation, but also contribute to an immunosuppressive tumor microenvironment. Furthermore, the CD73/adenosine pathway can also limit the immune-activating effects of cytotoxic therapies by degrading the pro-inflammatory danger molecule ATP, which is released into the tumor microenvironment and normal lung tissue upon therapy-induced cell damage. Thus, while targeting CD73 may enhance the efficacy of radio-immunotherapies in cancer treatment by mitigating tumor immune escape and improving immune-mediated tumor killing, it also raises concerns about increased immune-related adverse events (irAEs) in the normal tissue. In fact, combined radio-immunotherapies bear an increased risk of irAEs in the lungs, and additional pharmacologic inhibition of CD73 may further enhance the risk of overwhelming or overlapping pulmonary toxicity and thereby limit therapy outcome. This review explores how therapeutic interventions targeting CD73/adenosine dynamics could enhance radiation-induced immune activation in combined radio-immunotherapies, whilst potentially driving irAEs in the lung. We specifically investigate the interactions between radiotherapy and the CD73/adenosine pathway in radiation pneumonitis. Additionally, we compare the incidence of (radiation) pneumonitis reported in relevant trials to determine if there is an increased risk of irAEs in the clinical setting. By understanding these dynamics, we aim to inform future strategies for optimizing radio-immunotherapy regimens, ensuring effective cancer control while preserving pulmonary integrity and patient quality of life.

Discovery of cancer immunogenic chemotherapeutics represents an emerging, highly promising direction for cancer treatment that uses a chemical drug to achieve the efficacy of both chemotherapy and immunotherapy. Herein, we report a high-throughput screening platform and the subsequent discovery of a new class of cancer immunogenic chemotherapeutic leads. Our platform integrates informatics-based activity metabolomics for the rapid identification of microbial natural products with both novel structures and potent activities. Additionally, we demonstrate the use of microcrystal electron diffraction (MicroED) for direct structure elucidation of lead compounds from partially purified mixtures. Using this strategy to screen geographically and phylogenetically diverse microbial metabolites against pseudomyxoma peritonei, a rare and severe cancer, we discovered a new class of leads, aspercyclicins. The aspercyclicins feature an unprecedented tightly packed polycyclic polyketide scaffold that comprises continuous fused, bridged, and spiro rings. The biogenesis of aspercyclicins involves two distinct biosynthetic pathways, leading to formation of chimeric compounds that cannot be predicted by bottom-up approaches mining natural product biosynthetic genes. With comparable potency to some clinically used anticancer drugs, aspercyclicins are active against multiple cancer cell types by inducing immunogenic cell death (ICD), including the release of damage-associated molecular patterns and subsequent phagocytosis of cancer cells. The broad-spectrum ICD-inducing activity of aspercyclicins, combined with their low toxicity to normal cells, represents a new class of potential cancer immunogenic chemotherapeutics and, particularly, the first drug lead for pseudomyxoma peritonei treatment.

X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a stress-inducible tumor suppressor that is commonly inactivated in multiple types of human malignancies. Nevertheless, the molecular basis for the XAF1-mediated tumor suppression remains largely undefined. Here, we report that XAF1 is secreted from cells under various cytotoxic stress conditions and activates T cell-mediated tumor surveillance. In cancer cells exposed to interferon -γ, tumor necrosis factor -α, and etoposide, XAF1 is elevated and actively secreted through the unconventional endo-lysosomal trafficking pathway and the zinc finger 4 domain of XAF1 plays an essential for this secretion. Secreted XAF1 is internalized into nearby T cells through clathrin-mediated endocytosis and stimulates proliferation, migration, and tumor infiltration of T cells. Internalized XAF1 activates RAF-MEK-ERK signaling through the direct interaction with and phosphorylation of lymphocyte-specific protein tyrosine kinase. In response to interferon -γ injection, Xaf1+/+ tumors display significantly higher regression rate and T cell infiltration compared to Xaf1-/- tumors while Xaf1-/- tumors are markedly reduced by injection of recombinant Xaf1. XAF1 expression is associated with overall survival in T cell-enriched cancer patients and also correlates with prognosis in T cell-based immunotherapies. Together, our study identifies XAF1 as a novel secretory immune-modulatory tumor suppressor, illuminating the mechanistic consequence of its inactivation in tumorigenesis.

Immunotherapy is an emerging strategy in cancer therapeutics aimed at modulating the immune system to inhibit pro-tumor pathways and increase a tumor's sensitivity to chemotherapy. Several clinically approved immunotherapy treatments, such as monoclonal antibody treatments, have been successful in solid tumors such as breast, colorectal, and pancreatic. However, an outstanding challenge of these strategies is tumor cell resistance. One target of interest for immune cell modulation is targeting macrophages that enter the tumor microenvironment. More specifically, an immune checkpoint of interest is CD47. CD47 is a transmembrane protein that inhibits phagocytic activity by acting as a "don't eat me" signal. In both mice and humans, healthy cells can express CD47, while solid malignancies like colorectal and breast cancer express it most strongly.

Analysis of literature data on the physiological and functional roles of tissue-resident macrophages, along with the structure and mechanisms of action of the CD47 pathway was explored. We also explored how CD47 can influence different aspects of the tumor microenvironment (i.e. cellular metabolism and hypoxia) in addition to current clinical strategies and challenges associated with targeting CD47.

Overall, it was discovered that CD47 is overexpressed in a variety of cancer types in addition to normal tissue, making it a promising treatment regimen to enhance the capability of macrophages to phagocytose tumor cells. However, treatment efficacy is varied in pre-clinical and clinical models due to various challenges such as off-target effects.

This review emphasizes the diverse functionality of macrophages in normal and cancerous tissue, while also emphasizing the importance of macrophage targeting and their clinical significance.

Acetaminophen (APAP)-induced hepatotoxicity is a major cause of acute liver failure (ALF), during which autophagy is triggered as a cellular defense mechanism. Shaoyao-Gancao Decoction (SGD), a traditional prescription in Chinese Medicine, is renowned for its therapeutic effects on liver diseases. However, the efficacy and mechanisms of SGD in treating APAP-induced liver injury remain underexplored.

This study aims to provide robust evidence regarding the protective effects of SGD against APAP overdose in vitro and in vivo, as well as to elucidate its hepatoprotective mechanisms and active components.

The hepatoprotective mechanisms and active components of SGD were investigated through a combination of in vivo and in vitro experiments.

The protective effects of SGD on APAP-induced liver injury were assessed using a murine model and primary hepatocytes. RNA sequencing and subsequent experimental validations were conducted to uncover the underlying mechanisms of SGD's hepatoprotective actions. Comprehensive chemical profiling of SGD was performed using UHPLC-Q-Exactive Orbitrap HRMS to identify potential active ingredients. Immunohistochemistry, immunofluorescence, quantitative real-time PCR (qPCR), western blotting, enzyme-linked immunosorbent assay (ELISA), and flow cytometry were utilized to investigate the specific cellular changes in liver tissues and hepatocytes influenced by SGD.

SGD was observed to mitigate APAP-induced mitochondrial damage, inflammation, and necrosis by promoting mitochondrial autophagy. The inhibition of autophagy negated the hepatoprotective effects of SGD. Additionally, a detailed characterization of SGD's chemical composition revealed that Licoisoflavone B, Liquiritin, Liquiritin apioside, Licorice saponin G2 and Paeoniflorin Sulfit were potentially critical compounds in the regulation of autophagy and mitophagy.

Our findings demonstrate that SGD promotes autophagy/mitophagy, which effectively mitigates APAP-induced hepatotoxicity, suggesting SGD's potential as a promising therapeutic agent for APAP-induced liver injury.

Immunotherapy resistance poses a significant challenge in oncology, necessitating novel strategies to enhance the therapeutic efficacy. Immunogenic cell death (ICD), including necroptosis, pyroptosis and ferroptosis, triggers the release of tumor-associated antigens and numerous bioactive molecules. This release can potentiate a host immune response, thereby overcoming resistance to immunotherapy. Nanoparticles (NPs) with their biocompatible and immunomodulatory properties, are emerging as promising vehicles for the delivery of ICD-inducing agents and immune-stimulatory adjuvants to enhance immune cells tumoral infiltration and augment immunotherapy efficacy. This review explores the mechanisms underlying immunotherapy resistance, and offers an in-depth examination of ICD, including its principles and diverse modalities of cell death that contribute to it. We also provide a thorough overview of how NPs are being utilized to trigger ICD and bolster antitumor immunity. Lastly, we highlight the potential of NPs in combination with immunotherapy to revolutionize cancer treatment.

Recombinant human type 5 adenovirus (H101) is an oncolytic virus used to treat nasopharyngeal carcinoma. Owing to the deletion of the E1B-55kD and E3 regions, H101 is believed to selectively inhibit nasopharyngeal carcinoma. Whether H101 inhibits other type of tumors via different mechanisms remains unclear. In this study we investigated the effects of H101 on melanomas. We established B16F10 melanoma xenograft mouse model, and treated the mice with H101 (1 × 108 TCID50) via intratumoral injection for five consecutive days. We found that H101 treatment significantly inhibited B16F10 melanoma growth in the mice. H101 treatment significantly increased the infiltration of CD8+ T cells and reduced the proportion of M2-type macrophages. We demonstrated that H101 exhibited low cytotoxicity against B16F10 cells, but the endothelial cells were more sensitive to H101 treatment. H101 induced endothelial cell pyroptosis in a caspase-1/GSDMD-dependent manner. Furthermore, we showed that the combination of H101 with the immune checkpoint inhibitor PD-L1 antibody (10 mg/kg, i.p., every three days for three times) exerted synergic suppression on B16F10 tumor growth in the mice. This study demonstrates that, in addition to oncolysis, H101 inhibits melanoma growth by promoting anti-tumor immunity and inducing pyroptosis of vascular endothelial cells.

This article reviews the contemporary understanding of the functional role of connexins in intercellular communications, their involvement in maintaining cellular and tissue homeostasis, and in aging-associated respiratory disease pathogenesis. Connexins are discussed as potential therapeutic targets. The review particularly focuses on the involvement of gap junction connexins and hemichannels in the transfer of calcium ions, metabolite molecules, ATP, and mitochondria through the cell membrane. Various disorders in the regulation of intercellular communication can heavily contribute to the pathogenesis of multiple diseases, including respiratory system diseases. A deeper understanding of molecular mechanisms underlying the activities of various connexins in gap junction channels will enable the prospective development of therapeutic approaches by either inhibiting or stimulating the activities of a certain connexin, while considering its critical functions in intercellular communications on the whole.

According to the widely accepted "three Es" model, the host immune system eliminates malignant cell precursors and contains microscopic neoplasms in a dynamic equilibrium, preventing cancer outgrowth until neoplastic cells acquire genetic or epigenetic alterations that enable immune escape. This immunoevasive phenotype originates from various mechanisms that can be classified under a novel "three Cs" conceptual framework: (1) camouflage, which hides cancer cells from immune recognition, (2) coercion, which directly or indirectly interferes with immune effector cells, and (3) cytoprotection, which shields malignant cells from immune cytotoxicity. Blocking the ability of neoplastic cells to evade the host immune system is crucial for increasing the efficacy of modern immunotherapy and conventional therapeutic strategies that ultimately activate anticancer immunosurveillance. Here, we review key hallmarks of cancer immune evasion under the "three Cs" framework and discuss promising strategies targeting such immunoevasive mechanisms.

Discovery of cancer immunogenic chemotherapeutics represents an emerging, highly promising direction for cancer treatment that uses a chemical drug to achieve the efficacy of both chemotherapy and immunotherapy. Herein we report a high-throughput screening platform and the subsequent discovery of a new class of cancer immunogenic chemotherapeutic leads. Our platform integrates informatics-based activity metabolomics for rapid identification of microbial natural products with both novel structures and potent activities. Additionally, we demonstrate the use of microcrystal electron diffraction (MicroED) for direct structure elucidation of the lead compounds from partially purified mixtures. Using this strategy to screen geographically and phylogenetically diverse microbial metabolites against pseudomyxoma peritonei, a rare and severe cancer, we discovered a new class of leads, aspercyclicins. The aspercyclicins feature an unprecedented tightly packed polycyclic polyketide scaffold that comprises continuous fused, bridged, and spiro rings. The biogenesis of aspercyclicins involves two distinct biosynthetic pathways, leading to formation of chimeric compounds that cannot be predicted by bottom-up approaches mining natural products biosynthetic genes. With comparable potency to some clinically used anticancer drugs, aspercyclicins are active against multiple cancer cell types by inducing immunogenic cell death (ICD), including the release of damage-associated molecular patterns and subsequent phagocytosis of cancer cells. The broad-spectrum ICD-inducing activity of aspercyclicins, combined with their low toxicity to normal cells, represents a new class of potential cancer immunogenic chemotherapeutics and particularly the first drug lead for pseudomyxoma peritonei treatment.

Atherosclerosis (AS) is a chronic inflammatory disease primarily affecting large and medium-sized arterial vessels, characterized by lipoprotein disorders, intimal thickening, smooth muscle cell proliferation, and the formation of vulnerable plaques. Macrophages (MΦs) play a vital role in the inflammatory response throughout all stages of atherosclerotic development and are considered significant therapeutic targets. In early lesions, macrophage efferocytosis rapidly eliminates harmful cells. However, impaired efferocytosis in advanced plaques perpetuates the inflammatory microenvironment of AS. Defective efferocytosis has emerged as a key factor in atherosclerotic pathogenesis and the progression to severe cardiovascular disease. Herein, this review probes into investigate the potential mechanisms at the cellular, molecular, and organelle levels underlying defective macrophage efferocytosis in advanced lesion plaques. In the inflammatory microenvironments of AS with interactions among diverse inflammatory immune cells, impaired macrophage efferocytosis is strongly linked to multiple factors, such as a lower absolute number of phagocytes, the aberrant expression of crucial molecules, and impaired mitochondrial energy provision in phagocytes. Thus, focusing on molecular targets to enhance macrophage efferocytosis or targeting mitochondrial therapy to restore macrophage metabolism homeostasis has emerged as a potential strategy to mitigate the progression of advanced atherosclerotic plaque, providing various treatment options.

Cardiovascular disease is the leading cause of death worldwide, and it commonly results from atherosclerotic plaque progression. One of the increasingly recognized drivers of atherosclerosis is dysfunctional efferocytosis, a homeostatic mechanism responsible for the clearance of dead cells and the resolution of inflammation. In atherosclerosis, the capacity of phagocytes to participate in efferocytosis is hampered, leading to the accumulation of apoptotic and necrotic tissue within the plaque, which results in enlargement of the necrotic core, increased luminal stenosis and plaque inflammation, and predisposition to plaque rupture or erosion. In this Review, we describe the different forms of programmed cell death that can occur in the atherosclerotic plaque and highlight the efferocytic machinery that is normally implicated in cardiovascular physiology. We then discuss the mechanisms by which efferocytosis fails in atherosclerosis and other cardiovascular and cardiometabolic diseases, including myocardial infarction and diabetes mellitus, and discuss therapeutic approaches that might reverse this pathological process.

Immunotherapy is a rapidly developing and effective strategy for cancer therapy. Among various immunotherapy approaches, peptides have garnered significant attention due to their potent immunomodulatory effects. In particular, melittin emerged as a promising candidate to enhance cancer immunotherapy by inducing immunogenic cell death, promoting the maturation of antigen-presenting cells, activating T cells, enhancing the infiltration and cytotoxicity of effector lymphocytes, and modulating macrophage phenotypes for relieving immunosuppression. However, the clinical application of melittin is limited by poor targeting and systemic toxicity. To overcome these challenges, melittin has been incorporated into biomaterials and related nanotechnologies, resulting in extended circulation time in vivo, improved targeting, reduced adverse effects, and enhanced anti-cancer immunological action. This review provides an in-depth analysis of the immunomodulatory effects of melittin-incorporated nanomedicines and examines their development and challenges for clinical cancer immunotherapy.

Glycolysis is a highly conserved metabolic pathway responsible for the anaerobic production of adenosine triphosphate (ATP) from the breakdown of glucose molecules. While serving as a primary metabolic pathway in prokaryotes, glycolysis is also utilized by respiring eukaryotic cells, providing pyruvate to fuel oxidative metabolism. Furthermore, glycolysis is the primary source of ATP production in multiple cellular states (e.g., hypoxia) and is particularly important in maintaining bioenergetic homeostasis in the most abundant cell type in the human body, the erythrocyte. Beyond its role in ATP production, glycolysis also functions as a signaling hub, producing several metabolic intermediates which serve roles in both signaling and metabolic processes. These signals emanating from the glycolytic pathway can profoundly impact cell function, phenotype, and fate and have previously been overlooked. In this review, we will discuss the role of the glycolytic pathway as a source of signaling molecules in eukaryotic cells, emphasizing the newfound recognition of glycolysis' multifaceted nature and its importance in maintaining cellular homeostasis, beyond its traditional role in ATP synthesis.

Radiotherapy (RT) plays a key role in the tumour microenvironment (TME), impacting the immune response via cellular and humoral immunity. RT can induce local immunity to modify the TME. It can stimulate dendritic cell maturation and T-cell infiltration. Moreover, B cells, macrophages and other immune cells may also be affected. Tertiary lymphoid structure (TLS) is a unique structure within the TME and a class of aggregates containing T cells, B cells and other immune cells. The maturation of TLS is determined by the presence of mature dendritic cells, the density of TLS is determined by the number of immune cells. TLS maturation and density both affect the antitumour immune response in the TME. This review summarized the recent research on the impact and the role of RT on TLS, including the changes of TLS components and formation conditions and the mechanism of how RT affects TLS and transforms the TME. RT may promote TLS maturation and density to modify the TME regarding enhanced antitumour immunity.

Metabolic dysfunction-associated steatohepatitis (MASH) is a highly prevalent liver disease globally, with a significant risk of progressing to cirrhosis and even liver cancer. Efferocytosis, a process implicated in a broad spectrum of chronic inflammatory disorders, has been reported to be associated with the pathogenesis of MASH; however, its precise role remains obscure. Thus, we aimed to identify and validate efferocytosis linked signatures for detection of MASH.

We retrieved gene expression patterns of MASH from the GEO database and then focused on assessing the differential expression of efferocytosis-related genes (EFRGs) between MASH and control groups. This analysis was followed by a series of in-depth investigations, including protein-protein interaction (PPI), correlation analysis, and functional enrichment analysis, to uncover the molecular interactions and pathways at play. To screen for biomarkers for diagnosis, we applied machine learning algorithm to identify hub genes and constructed a clinical predictive model. Additionally, we conducted immune infiltration and single-cell transcriptome analyses in both MASH and control samples, providing insights into the immune cell landscape and cellular heterogeneity in these conditions.

This research pinpointed 39 genes exhibiting a robust correlation with efferocytosis in MASH. Among these, five potential diagnostic biomarkers-TREM2, TIMD4, STAB1, C1QC, and DYNLT1-were screened using two distinct machine learning models. Subsequent external validation and animal experimentation validated the upregulation of TREM2 and downregulation of TIMD4 in MASH samples. Notably, both TREM2 and TIMD4 demonstrated area under the curve (AUC) values exceeding 0.9, underscoring their significant potential in facilitating the diagnosis of MASH.

Our study comprehensively elucidated the relationship between MASH and efferocytosis, constructing a favorable diagnostic model. Furthermore, we identified potential therapeutic targets for MASH treatment and offered novel insights into unraveling the underlying mechanisms of this disease.

Tumor-associated macrophages (TAMs) exhibit antitumor or protumor responses related to inflammatory (or M1) and alternative (or M2) phenotypes, respectively. The P2X7 receptor plays a key role in macrophage polarization, influencing inflammation and immunosuppression. In this study, we investigated the role of the P2X7 receptor in TAMs. Using P2X7 receptor-deficient macrophages, we analyzed gene expression profiles and their implications for neuroblastoma invasion and chemoresistance. Our results showed that P2X7 receptor deficiency altered the expression of classical polarization markers, such as nitric oxide synthase 2 (Nos2) and tumor necrosis factor-α (Tnf), as well as alternative phenotype markers, including mannose receptor C-type 1 (Mrc1) and arginase 1 (Arg1). P2X7 deficiency also influenced the expression of the ectonucleotidases Entpd1 and Nt5e and other purinergic receptors, especially P2ry2, suggesting compensatory mechanisms involved in macrophage polarization. In particular, TAMs deficient in P2X7 showed a phenotype with characteristics intermideiate between resting macrophages (M0) and M1 polarization rather than the M2-type phenotype like and wild-type TAM macrophages. In addition, P2rx7-/- TAMs regulated the expression of P2X7 receptor isoforms in neuroblastoma cells, with downregulation of the P2X7 A and B isoforms leading to a decrease in chemotherapy-induced cell death. However, TAMs expressing P2X7 downregulated only the B isoform, suggesting that TAMs play a role in modulating tumor behavior through P2X7 receptor isoform regulation. Taken together, our data underscore the regulatory function of the P2X7 receptor in orchestrating alternative macrophage polarization and in the interplay between tumor cells and TAMs. These findings help to clarify the complex interplay of purinergic signaling in cancer progression and open up avenues for future research and therapeutic interventions.

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor whose expression regulates immune cell differentiation. Single-cell transcriptomic profiling was used to ascertain the heterogeneity of AHR expression in human B cell subpopulations. We identified a unique population of B cells marked by expression of AHR, CD9, and myeloid genes such as CD14 and CXCL8. Results were confirmed directly in human PBMCs and purified B cells at the protein level. TLR9 signaling induced CD14, CD9, and IL-8 protein expression in CD19+ B cells. CD14-expressing CD9+ B cells also highly expressed AHR and atypical B cell markers such as CD11c and TBET. In patients with active lupus disease, CD14+ and CD9+ B cells are dysregulated, with loss of CD9+ B cells strongly predicting disease severity and demonstrating the relevance of CD9+ B cells in systemic lupus erythematosus and autoimmune disease.

P2 purinergic receptor expression is dysregulated in multiple cancer subtypes and is associated with worse outcomes. Studies identify roles for P2 purinergic receptors in tumor cells that drive disease aggressiveness. There is also sufficient evidence that P2 purinergic receptor expression within the tumor microenvironment (TME) is critical for disease initiation and progression. Immune cells constitute a significant component of the TME and display both tumorigenic and anti-tumorigenic potential. Studies pre-dating the investigation of P2 purinergic receptors in cancer identify P2 receptor expression on multiple immune cells including macrophages, neutrophils, T-cells, and dendritic cells; all of which are implicated in tumor initiation, tumor promotion, or response to treatment. Herein, we discuss P2 purinergic receptor expression and function in tumor-related immune cells. We provide a rationale for further investigations of P2 purinergic receptors within the TME to better define the mechanistic pathways of inflammation-mediate tumorigenesis and explore P2 purinergic receptors as potential targets for novel immunotherapeutic approaches.

Alveolar epithelial Type II (ATII) cells are closely associated with early events of Idiopathic pulmonary fibrosis (IPF). Proteostasis dysfunction, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction are known causes of decreased proliferation of alveolar epithelial cells and the secretion of pro-fibrotic mediators. Here, a large body of evidence is systematized and a cascade relationship between protein homeostasis, endoplasmic reticulum stress, mitochondrial dysfunction, and fibrotropic cytokines is proposed, providing a theoretical basis for ATII cells dysfunction as a possible pathophysiological initiating event for idiopathic pulmonary fibrosis.

After ischaemic cerebral vascular injury, efferocytosis-a process known as the efficient clearance of apoptotic cells (ACs) by various phagocytes in both physiological and pathological states-is crucial for maintaining central nervous system (CNS) homeostasis and regaining prognosis. The mechanisms of efferocytosis in ischaemic stroke and its influence on preventing inflammation progression from secondary injury were still not fully understood, despite the fact that the fundamental process of efferocytosis has been described in a series of phases, including AC recognition, phagocyte engulfment, and subsequent degradation. The genetic reprogramming of macrophages and brain-resident microglia after an ischaemic stroke has been equated by some researchers to that of the peripheral blood and brain. Based on previous studies, some molecules, such as signal transducer and activator of transcription 6 (STAT6), peroxisome proliferator-activated receptor γ (PPARG), CD300A, and sigma non-opioid intracellular receptor 1 (SIGMAR1), were discovered to be largely associated with aspects of apoptotic cell elimination and accompanying neuroinflammation, such as inflammatory cytokine release, phenotype transformation, and suppressing of antigen presentation. Exacerbated stroke outcomes are brought on by defective efferocytosis and improper modulation of pertinent signalling pathways in blood-borne macrophages and brain microglia, which also results in subsequent tissue inflammatory damage. This review focuses on recent researches which contain a number of recently discovered mechanisms, such as studies on the relationship between benign efferocytosis and the regulation of inflammation in ischaemic stroke, the roles of some risk factors in disease progression, and current immune approaches that aim to promote efferocytosis to treat some autoimmune diseases. Understanding these pathways provides insight into novel pathophysiological processes and fresh characteristics, which can be used to build cerebral ischaemia targeting techniques.